Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations
- University of Michigan, United States
- Oregon National Primate Research Center, United States
- Novo Nordisk Research Center, United States
Abstract
The ventromedial hypothalamic nucleus (VMH) controls diverse behaviors and physiologic functions, suggesting the existence of multiple VMH neural subtypes with distinct functions. Combing Translating Ribosome Affinity Purification with RNA sequencing (TRAP-seq) data with snRNA-seq data, we identified 24 mouse VMH neuron clusters. Further analysis, including snRNA-seq data from macaque tissue, defined a more tractable VMH parceling scheme consisting of 6 major genetically- and anatomically-differentiated VMH neuron classes with good cross-species conservation. In addition to two major ventrolateral classes, we identified three distinct classes of dorsomedial VMH neurons. Consistent with previously-suggested unique roles for leptin receptor (Lepr)-expressing VMH neurons, Lepr expression marked a single dorsomedial class. We also identified a class of glutamatergic VMH neurons that resides in the tuberal region, anterolateral to the neuroanatomical core of the VMH. This atlas of conserved VMH neuron populations provides an unbiased starting point for the analysis of VMH circuitry and function.
Data availability
Sequencing data have been deposited in GEO under accession code GSE172207
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Cross-Species Analysis Defines the Conservation of Anatomically-Segregated VMH Neuron PopulationsNCBI Gene Expression Omnibus, GSE172207.
Article and author information
Author details
Funding
National Institutes of Health (dk056731)
- Martin G Myers Jr
Novo Nordisk
- Martin G Myers Jr
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice used in this study were maintained in accordance with University of Michigan Institutional Animal Care and Use Committee (IACUC), Association for the Assessment and Approval of Laboratory Animal Care (AAALAC) and National Institutes of Health (NIH) guidelines under protocol number PRO00007438 (PI Myers).Nonhuman primate tissue was obtained post-mortem from the Tissue Distribution Program at ONPRC. Animal care is in accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and animal facilities at the Oregon National Primate Research Center (ONPRC) are accredited by the American Association for Accreditation of Laboratory Animal Care International. ONPRC does not provide protocol numbers for security reasons.
Reviewing Editor
- Ana Domingos, University of Oxford, United Kingdom
Version history
- Received: April 2, 2021
- Accepted: May 14, 2021
- Accepted Manuscript published: May 21, 2021 (version 1)
- Accepted Manuscript updated: May 24, 2021 (version 2)
- Version of Record published: June 7, 2021 (version 3)
Copyright
© 2021, Affinati et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cross-Species analysis defines the conservation of anatomically-segregated VMH neuron populations
eLife 10:e69065.
https://doi.org/10.7554/eLife.69065
Further reading
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The joint storage and reciprocal retrieval of learnt associated signals are presumably encoded by associative memory cells. In the accumulation and enrichment of memory contents in lifespan, a signal often becomes a core signal associatively shared for other signals. One specific group of associative memory neurons that encode this core signal likely interconnects multiple groups of associative memory neurons that encode these other signals for their joint storage and reciprocal retrieval. We have examined this hypothesis in a mouse model of associative learning by pairing the whisker tactile signal sequentially with the olfactory signal, the gustatory signal, and the tail-heating signal. Mice experienced this associative learning show the whisker fluctuation induced by olfactory, gustatory, and tail-heating signals, or the other way around, that is, memories to multi-modal associated signals featured by their reciprocal retrievals. Barrel cortical neurons in these mice become able to encode olfactory, gustatory, and tail-heating signals alongside the whisker signal. Barrel cortical neurons interconnect piriform, S1-Tr, and gustatory cortical neurons. With the barrel cortex as the hub, the indirect activation occurs among piriform, gustatory, and S1-Tr cortices for the second-order associative memory. These associative memory neurons recruited to encode multi-modal signals in the barrel cortex for associative memory are downregulated by neuroligin-3 knockdown. Thus, associative memory neurons can be recruited as the core cellular substrate to memorize multiple associated signals for the first-order and the second-order of associative memories by neuroligin-3-mediated synapse formation, which constitutes neuronal substrates of cognitive activities in the field of memoriology.
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- Chromosomes and Gene Expression
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Mathys et al. conducted the first single-nucleus RNA-seq (snRNA-seq) study of Alzheimer’s disease (AD) (Mathys et al., 2019). With bulk RNA-seq, changes in gene expression across cell types can be lost, potentially masking the differentially expressed genes (DEGs) across different cell types. Through the use of single-cell techniques, the authors benefitted from increased resolution with the potential to uncover cell type-specific DEGs in AD for the first time. However, there were limitations in both their data processing and quality control and their differential expression analysis. Here, we correct these issues and use best-practice approaches to snRNA-seq differential expression, resulting in 549 times fewer DEGs at a false discovery rate of 0.05. Thus, this study highlights the impact of quality control and differential analysis methods on the discovery of disease-associated genes and aims to refocus the AD research field away from spuriously identified genes.
